1. Field of the Invention
The present invention relates generally to methods and compositions that can be used to promote bone and joint health through amelioration, stabilization or repair of damage associated with various pathophysiological conditions.
2. Description of the Related Art
Millions daily suffer damage to joint and bone tissues, either from the normal bumps and bruises of every day life or as a result of various disease conditions. Osteoarthritis, rheumatoid arthritis, and osteoporosis represent the most prevalent diseases influencing bone and joint health. Furthermore, other diseases not generally associated with bone or joint health, such as systemic lupus erythematosus, for example, may have elements affecting bones or joints structure and function.
Osteoarthritis (OA) is an age-related joint disorder that affects more than 40 million Americans (Hinton et al, “Osteoarthritis: Diagnosis and therapeutic considerations.” Am Fam Physician. 65:841-8, 2002; Lawrence et al, “Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.” Arthritis Rheum. 41:778-99; 2004). The disease affects the entire joint structure, and is characterized pathologically by focal areas of articular cartilage loss in synovial joints, varying degrees of osteophyte formation (bony outgrowths at the cartilage margins), subchondral bone change, and synovitis. Although OA was historically regarded solely as a degenerative form of arthritis, there is increasing evidence for inflammation as a vital component of OA. Signs of synovial inflammation are present in the many symptoms of OA: joint swelling and effusion, stiffness and occasional redness, especially at proximal and distal interpharyngeal joints. Further, elevated levels of inflammatory cytokines (interleukin-1 beta [IL-1β] and tumor necrosis factor alpha [TNFα]) have been observed in OA synovial fluid. These cytokines, which are primarily synthesized by chondrocytes, appear to play a major part in the destruction of cartilage tissue through the induction of matrix metalloproteinases (MMPs), nitric oxide (NO) and prostaglandin E2 (PGE2). (see, for example, Dieppe & Lohmander, “Pathogenesis and management of pain in osteoarthritis.” Lancet. 365:965-73; 2005; Felson et al, “Osteoarthritis: New insights”. Ann Intern Med. 133:635-46; 2000; Goldring, “The role of the chondrocyte in osteoarthritis.” Arthritis Rheum 43:1916-26; 2000; van der Kraan & van der Berg, “Anabolic and destructive mediators in osteoarthritis.” Curr Opin Nutr Metab Care. 3:205-11; 2000; Pelletier et al, “Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets.” Arthritis Rheum. 44:1237-47; 2001; Iannorme F, Lapadula G. “The pathophysiology of osteoarthritis.” Aging Clin Exp Res. 15:364-72; 2003).
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that affects 1% of the American population, and approximately three times as many women as men are affected by this disorder. RA, which can be a self-limiting condition or a debilitating chronic disease leading to joint destruction and deformity, is characterized by joint inflammation, and the predominant symptoms include pain, stiffness and swelling of peripheral joints. (see, for example, Lee D M, Weinblatt M E. “Rheumatoid arthritis”. Lancet. 358:903-11; 2001; Rindfleisch J A, Muller D. “Diagnosis and management of rheumatoid arthritis.” Am Fam Physician. 72:1049-50; 2005; and Doan T, and Massarotti E. “Rheumatoid arthritis: An overview of new and emerging therapies.” J Clin Pharmacol. 45:751-62; 2005).
The sequence of events in RA is thought to be initiated by CD4+ T cells, which upon recognizing arthritogenic antigens in synovial tissue, activate macrophages, monocytes and synovial fibroblasts. The activated macrophages, monocytes and synovial fibroblasts then secrete numerous inflammatory cytokines like interleukin-1 (IL-1), IL-6 and tumor necrosis factor α; in addition, these activated cells also secrete matrix metalloproteinases, which are responsible for the proteolytic breakdown of bone and cartilage tissue. Other mediators of inflammation induced by the pro-inflammatory cytokines, and which contribute to the pathology in affected joints include prostaglandin E2 (PGE2) and nitric oxide. (see, for example, Lee D M, Weinblatt M E., Rheumatoid arthritis. “Lancet. 358:903-11; 2001; Bingham 3rd CO. “The pathogenesis of rheumatoid arthritis: Pivotal cytokines involved in bone degradation and inflammation.” J Rheumatol. 29 (suppl 65):3-9; 2002; and Doan T, and Massarotti E. “Rheumatoid arthritis: An overview of new and emerging therapies.” J Clin Pharmacol. 45:751-62; 2005).
Osteoporosis is a disease characterized by low bone mass and deterioration of bone structure resulting in bone fragility and increased risk of fracture. The World Health Organization has defined osteoporosis as a bone mineral density (BMD) value more than 2.5 standard deviations below the mean for normal young White women. Individuals with osteoporosis are at high risk of suffering one or more fractures, injuries that can often be physically debilitating and potentially lead to a downward spiral in physical and mental health. There are a variety of different types of osteoporosis. “Primary osteoporosis” is the most common form of the disease and is characterized as osteoporosis that is not caused by some other specific disorder. If the bone loss has been caused by specific diseases or medications then it is referred to as “secondary osteoporosis.”
According to the Surgeon General of the United States “the 1.5 million osteoporotic fractures in the United States each year lead to more than half a million hospitalizations, over 800,000 emergency room encounters, more than 2,600,000 physician office visits, and the placement of nearly 180,000 individuals into nursing homes. Hip fractures are by far the most devastating type of fracture, accounting for about 300,000 hospitalizations each year. Caring for these fractures is expensive. Studies show that annual direct care expenditures for osteoporotic fractures range from $12 to $18 billion per year in 2002 dollars. Indirect costs (e.g., lost productivity for patients and caregivers) likely add billions of dollars to this figure. These costs could double or triple in the coming decades.” See “Bone Health and Osteoporosis: A Report of the Surgeon General (2004)” published at http://www.surgeongeneral.gov/library/bonehealth/content.html (last viewed on Feb. 26, 2008).
Newer methods and compositions for promoting bone and joint health are required since many of the conditions of impaired bone or joint health are or become chronic in nature, thereby necessitating long term therapies. One area for exploration would include botanical based products having proven long term histories of safe use. Two potential candidates are berberine and substituted 1,3-cyclopentadione compounds which may either be isolated from hops or derived from hops.
Berberine (7,8,13,13a-tetrahydro-9,10-dimethoxy-2,3-(methylenedioxy)-berbinium), an alkaloid most commonly associated with extracts from plants of the Berberis species, has a history of safety and has known widespread use in traditional medicine for the treatment of a number of conditions ranging from diabetes (See, for example, Leng, S H., et al., “Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion.” Acta Pharmacol Sin. 25 (4):496-502; 2004), or for protozoal, bacterial, or fungal infections (see, for example, Sabir, M., et al., “Experimental study of the antitrachoma action of berberine”, Indian J Med. Res. 64 (8): 1160-7, 1976; Mohan, M., et al., “Berberine in trachoma. (A clinical trial).” Indian J Opthalmol. 30 (2):69-75, 1982); Mekawi, M., “Effect of berberine alkaloid on cholera Vibro and its endotoxin.” J Egypt Med. Assoc. 49 (8):554-9, 1966; or Albal, M V., et al., “Clinical evaluation of berberine in mycotic infections.” Indian J Opthalmol. 34:91-2; 1986). Berberine has also been used septic shock and graft versus host disease (Upadhyay, S., et al., U.S. Pat. No. 6,291,483) and investigated for its anti-inflammatory properties as a potential arthritis treatment modality (Ivanovska, N., and Philipov, S., “Study on the anti-inflammatory action of Berberis vulgaris root extract, alkaloid fractions and pure alkaloids.”, Int. J. Immunopharmac., 18 (10: 553-561, 1996).
The inventors have previously reported on a number of compounds either isolated from hops or derived from hops (alpha acids, beta acids, prenylflavonoids, chalcones, isoalpha acids, and reduced isoalpha acids) which display activity against numerous conditions including inflammation, minor pain, and arthritic conditions (see, for example, U.S. 2003/0008021; US 2003/0113393; US 2004/0115290; or US 2004/0151792). The inventors have found and report herein among other things the unexpected results that berberine may act synergistically with substituted 1,3-cyclopentadione compounds which may either be isolated from hops or derived from hops to promote bone and joint health. The inventors additionally report on combinations of botanically derived compounds which may be used to promote joint and bone health.